With the attached powerpoint as the example, use the information from the attached journal and journal club and create a separate powerpoint that addresses the following questions:

What was the main purpose of the study?

The key findings?

What are the broader implications for the study’s findings?

FILE_9154.pdf
FILE_1641.docx
FILE_7391.pptx

The new england journal of medicine

n engl j med 391;2 nejm.org July 11, 2024 109

established in 1812 July 11, 2024 vol. 391 no. 2

From the University of New South Wales, Sydney (V.P.); the Division of Nephrolo- gy, University of Washington School of Medicine, Seattle, and Providence Medi- cal Research Center, Providence Inland Northwest Health, Spokane — both in Washington (K.R.T.); Steno Diabetes Cen- ter Copenhagen, Herlev (P.R.), the De- partment of Clinical Medicine, University of Copenhagen, Copenhagen (P.R.), and Novo Nordisk, Søborg (F.M.M.B., T.I., H.B.-T., N.L.L.) — all in Denmark; Stan- ford Center for Clinical Research, Depart- ment of Medicine, Stanford School of Medicine, Palo Alto, CA (K.W.M.); KfH Kidney Center, Munich, and University Hospital, Friedrich-Alexander University, Erlangen — both in Germany (J.F.E.M.); the Department of Medicine, American Heart Association Comprehensive Hyper- tension Center, University of Chicago Medi- cine, Chicago (G.B.); and AdventHealth Translational Research Institute, Orlando, FL (R.P.). Dr. Perkovic can be contacted at vlado . perkovic@ unsw . edu . au or at the Chancellery, University of New South Wales, Sydney, NSW 2052, Australia.

*The FLOW Trial Committees and Inves- tigators are listed in the Supplementary Appendix, available at NEJM.org.

This article was published on May 24, 2024, and updated on September 17, 2024, at NEJM.org.

BACKGROUND Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. METHODS We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albu- min measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creati- nine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a compos- ite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary out- comes were tested hierarchically. RESULTS Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific com- ponents of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). CONCLUSIONS Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.)

a bs tr ac t

Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes

Vlado Perkovic, M.B., B.S., Ph.D., Katherine R. Tuttle, M.D., Peter Rossing, M.D., D.M.Sc., Kenneth W. Mahaffey, M.D., Johannes F.E. Mann, M.D., George Bakris, M.D., Florian M.M. Baeres, M.D.,

Thomas Idorn, M.D., Ph.D., Heidrun Bosch-Traberg, M.D., Nanna Leonora Lausvig, M.Sc., and Richard Pratley, M.D., for the FLOW Trial Committees and Investigators*

CME

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society. Downloaded from nejm.org at Novo Nordisk–Bagsvaerd/Denmark on October 17, 2024. For personal use only.

http://clinicaltrials.gov/show/NCT03819153

n engl j med 391;2 nejm.org July 11, 2024110

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

More than half a billion people globally are affected by chronic kidney disease and are at high risk for kidney

failure, cardiovascular events, and death.1 Type 2 diabetes is the most frequent cause of chronic kidney disease in many countries. Renin–angio- tensin system (RAS) inhibitors,2,3 sodium–glucose cotransporter 2 (SGLT2) inhibitors, and finere- none have been shown to protect the kidneys and reduce the risk of adverse cardiovascular out- comes4-8 and therefore are guideline-directed med- ical therapies for chronic kidney disease in patients with type 2 diabetes.9,10 Nevertheless, many pa- tients continue to lose kidney function and go on to have kidney failure or to die, most com- monly from cardiovascular events. Thus, the ef- fects of therapies such as glucagon-like peptide 1 (GLP-1) receptor agonists are of great interest.11

The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial assessed the ef- ficacy and safety of subcutaneous semaglutide at a dose of 1.0 mg once weekly for the prevention of kidney failure, substantial loss of kidney func- tion, and death from kidney-related or cardiovas- cular causes in patients with type 2 diabetes and chronic kidney disease.

Me thods

Trial Design and Oversight

We published the design of this international, double-blind, randomized, placebo-controlled trial previously.12 The trial was overseen by an academ- ic-led steering committee (see the Supplementa- ry Appendix, available with the full text of this article at NEJM.org) in partnership with the trial sponsor, Novo Nordisk, which also managed trial operations. The trial steering committee provided overall leadership; oversaw trial design, conduct, and analysis; and was responsible for reporting the results. Analyses were conducted by the spon- sor and were independently verified with the use of the original data by Statogen Consulting. The first author wrote the first draft of the manu- script, and all the authors contributed to subse- quent revisions. Technical editorial assistance was provided by OpenHealth and funded by the sponsor. The authors had access to the full data set, made the decision to submit the manuscript for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol (available at NEJM.org).

Relevant approval from regulatory authorities and institutional review boards was obtained. Each participant provided written informed consent before undergoing any trial-related procedures.

Participants

Adults with type 2 diabetes (glycated hemoglo- bin level, ≤10%) were eligible for inclusion in the trial if they had high-risk chronic kidney disease and were receiving a stable maximal labeled dose (or the maximal dose without unacceptable side effects) of RAS inhibitors (angiotensin-convert- ing–enzyme inhibitor or angiotensin-receptor blocker). Kidney disease was defined by an esti- mated glomerular filtration rate (eGFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area (calculated with the serum creatinine level and the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 2009 formula,13 which were used to calculate all reported eGFR values unless otherwise indicated), with a urinary albu- min-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of greater than 300 and less than 5000 if the eGFR was 50 ml per minute per 1.73 m2 or higher or a urinary albumin-to-creatinine ratio of greater than 100 and less than 5000 if the eGFR was 25 to less than 50 ml per minute per 1.73 m2. Patients who were unable to receive RAS inhibition because of side effects were eligible for inclusion. A full list of inclusion and exclusion criteria, including a range of specific kidney dis- ease diagnoses, is provided in the Supplementary Appendix.

Trial Procedures

Eligible participants were randomly assigned in a 1:1 ratio to receive semaglutide or matching placebo with the use of a central interactive Web- based response system. The use of SGLT2 inhibi- tors and mineralocorticoid-receptor antagonists (MRAs) was permitted, and randomization was stratified according to SGLT2 inhibitor use at baseline. An 8-week dose-escalation regimen was used, with dose escalation (as long as unac- ceptable side effects did not occur) from 0.25 mg per week for 4 weeks and 0.5 mg per week for another 4 weeks, followed by a maintenance dose of 1.0 mg per week throughout the remain- der of the treatment period. If unacceptable ad- verse effects occurred, dose-escalation intervals could be extended, treatment could be paused,

A Quick Take is available at

NEJM.org

n engl j med 391;2 nejm.org July 11, 2024 111

Effects of Semaglutide on Chronic Kidney Disease

or lower maintenance doses could be used. Labo- ratory-based inclusion criteria were based on local laboratory values recorded within 90 days before the screening visit or central laboratory values recorded at screening or at optional prescreen- ing visits.

Trial Outcomes

The primary outcome was major kidney disease events, a composite of onset of kidney failure (ini- tiation of long-term dialysis, kidney transplanta- tion, or a reduction in the eGFR to <15 ml per minute per 1.73 m2 sustained for ≥28 days), a sustained (for ≥28 days) 50% or greater reduc- tion in eGFR from baseline, or death from kid- ney-related or cardiovascular causes. Three key confirmatory secondary outcomes were defined and assessed with the use of a formal hierarchi- cal testing strategy: total eGFR slope (i.e., the annual rate of change in eGFR from randomiza- tion to the end of the trial); major cardiovascular events (a composite of nonfatal myocardial in- farction, nonfatal stroke, or death from cardio- vascular causes), assessed in a time-to-first-event analysis; and death from any cause. A range of additional supportive secondary, exploratory, and other outcomes were also prespecified and are listed in the Supplementary Appendix.

Safety was assessed by collecting data on all serious adverse events, adverse events leading to discontinuation of semaglutide or placebo, and adverse events of special interest. Primary and sec- ondary outcomes other than eGFR assessments derived from the central laboratory were adjudi- cated in a blinded fashion by an event adjudication committee (see the Supplementary Appendix).

Statistical Analysis

This trial was event driven. We calculated that a minimum of 854 primary-outcome events would provide 90% power to detect a 20% lower relative risk in the semaglutide group than in the placebo group at an overall one-sided significance level of 2.5%. An interim analysis of efficacy was planned for after two thirds of the total planned number of primary-outcome events had occurred.

Efficacy analyses were based on the intention- to-treat principle and included all unique partici- pants who underwent randomization, irrespective of adherence to semaglutide or placebo or chang- es to background medications. Time-to-first-event outcomes were analyzed with a stratified Cox

proportional-hazards model with randomization assignment (semaglutide or placebo) as a fixed factor and stratified according to SGLT2 inhibi- tor use at baseline. P values were obtained from a score test. For the primary outcome, the hazard ratio, 95% confidence interval, and P value were adjusted for the group sequential design with the use of likelihood-ratio ordering. The eGFR slope was analyzed with a linear mixed-effects model with randomization assignment, SGLT2 inhibitor use at baseline, time, and the interac- tion between randomization assignment and time as fixed effects, participant as a random intercept, and time as a random slope. Missing data were not imputed.

If superiority was confirmed for the primary outcome, testing of the confirmatory secondary outcomes was performed in a prespecified hier- archical order to ensure type I error control. To account for the prespecified interim analysis, the nominal significance level for the primary and confirmatory secondary outcomes was calculated with the Lan–DeMets alpha-spending function and the actual observed number of primary-out- come events available for the primary analysis. On the basis of the available number of events, the one-sided nominal significance level for the pri- mary and confirmatory secondary outcomes was updated to 0.0161 (equivalent to a two-sided level of 0.0322, which is used in this report). Details are provided in the Supplementary Appendix.

Continuous supportive secondary outcomes were assessed by analysis of covariance with the use of multiple imputation for missing values under a missing-at-random assumption. Analyses of supportive and exploratory outcomes were not adjusted for multiplicity, and confidence intervals for these outcomes should not be used in place of hypothesis testing. All statistical analyses were performed with SAS software, version 9.4 TS1M5 (SAS Institute).

R esult s

Trial Participants

The trial was conducted at 387 sites in 28 coun- tries (see the Supplementary Appendix), with re- cruitment occurring from June 2019 through May 2021. Among the 5581 screened candidates (Fig. S1 in the Supplementary Appendix), 3533 met the entry criteria and were randomly assigned to the semaglutide group (1767 participants) or the pla-

n engl j med 391;2 nejm.org July 11, 2024112

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Table 1. Characteristics of the Participants at Baseline.*

Characteristic Semaglutide (N = 1767)

Placebo (N = 1766)

Total (N = 3533)

Age — yr 66.6±9.0 66.7±9.0 66.6±9.0

Female sex — no. (%) 519 (29.4) 550 (31.1) 1069 (30.3)

Geographic region — no. (%)

Asia 478 (27.1) 434 (24.6) 912 (25.8)

Europe 472 (26.7) 491 (27.8) 963 (27.3)

North America 423 (23.9) 442 (25.0) 865 (24.5)

Other 394 (22.3) 399 (22.6) 793 (22.4)

Race or ethnic group — no. (%)†

White 1155 (65.4) 1168 (66.1) 2323 (65.8)

Asian 439 (24.8) 407 (23.0) 846 (23.9)

Black 78 (4.4) 82 (4.6) 160 (4.5)

Other 95 (5.4) 109 (6.2) 204 (5.8)

Hispanic or Latinx ethnic group — no. (%)†

Yes 273 (15.4) 283 (16.0) 556 (15.7)

No 1421 (80.4) 1411 (79.9) 2832 (80.2)

Not reported 73 (4.1) 72 (4.1) 145 (4.1)

Glycated hemoglobin level — % 7.8±1.3 7.8±1.3 7.8±1.3

Body-mass index‡ 31.9±6.1 32.0±6.5 32.0±6.3

Body weight — kg 89.5±19.8 89.8±21.2 89.6±20.5

Systolic blood pressure — mm Hg 138.9±16.1 138.4±15.4 138.6±15.8

Diastolic blood pressure — mm Hg 76.8±10.0 76.1±10.0 76.4±10.0

Diabetes duration — no. (%)

<15 yr 774 (43.8) 753 (42.6) 1527 (43.2)

≥15 yr 992 (56.1) 1013 (57.4) 2005 (56.8)

Previous myocardial infarction or stroke — no. (%) 405 (22.9) 403 (22.8) 808 (22.9)

Chronic heart failure — no. (%) 342 (19.4) 336 (19.0) 678 (19.2)

Smoking status — no. (%)§

Current smoker 223 (12.6) 206 (11.7) 429 (12.1)

Previous smoker 661 (37.4) 696 (39.4) 1357 (38.4)

Never smoked 883 (50.0) 864 (48.9) 1747 (49.4)

eGFR — ml/min/1.73 m2¶ 46.9±15.6 47.1±14.7 47.0±15.2

eGFR distribution — no. (%)¶

≥60 ml/min/1.73 m2 366 (20.7) 353 (20.0) 719 (20.4)

≥45 to <60 ml/min/1.73 m2 515 (29.1) 540 (30.6) 1055 (29.9)

≥30 to <45 ml/min/1.73 m2 667 (37.7) 691 (39.1) 1358 (38.4)

<30 ml/min/1.73 m2 218 (12.3) 182 (10.3) 400 (11.3)

Median urinary albumin-to-creatinine ratio‖ 582.3 557.8 567.6

Category of albuminuria — no. (%)**

A1, normoalbuminuria 52 (2.9) 57 (3.2) 109 (3.1)

A2, microalbuminuria 509 (28.8) 495 (28.0) 1004 (28.4)

A3, macroalbuminuria 1205 (68.2) 1214 (68.7) 2419 (68.5)

n engl j med 391;2 nejm.org July 11, 2024 113

Effects of Semaglutide on Chronic Kidney Disease

cebo group (1766 participants) and included in the analyses. Four participants underwent ran- domization more than once, and only the first randomization was included in analyses; one par- ticipant was excluded from the analysis because of a lack of adherence to Good Clinical Practice guidelines at the relevant site.

The baseline characteristics of the participants were well balanced between the groups (Table 1 and Table S1). The mean age was 66.6 years, and 1069 participants (30.3%) were women. The mean eGFR was 47.0 ml per minute per 1.73 m2, and the median urinary albumin-to-creatinine ratio (with albumin measured in milligrams and cre- atinine measured in grams) was 567.6. According to the Kidney Disease: Improving Global Out- comes risk calculators,14 68% of the participants were at very high risk for kidney disease pro- gression, kidney failure, cardiovascular events, or death. The participants in the trial were broadly representative of the relevant population

and consistent with those in previous trials,4,5,8 as described in Table S2.

A prespecified single interim analysis was triggered in October 2023 after approximately 570 primary-outcome events had accrued. An in- dependent data and safety monitoring committee reviewed the data and recommended early com- pletion of the trial for efficacy. This recommen- dation was accepted, participants were recalled for final visits, and the trial was completed with the final participant visit occurring on January 9, 2024. At the time of completion of the trial, the median participant follow-up was 3.4 years (range, 0 to 4.5). The trial was closed early at two sites in Russia that had been sanctioned by the sponsor, and 14 participants at the affected sites ended participation early. In total, 34 par- ticipants withdrew consent, and vital status was able to be confirmed at the end of trial for 3482 participants (98.6%). Semaglutide or placebo was permanently discontinued by 26% of participants

Characteristic Semaglutide (N = 1767)

Placebo (N = 1766)

Total (N = 3533)

Medication use — no. (%)

SGLT2 inhibitor 277 (15.7) 273 (15.5) 550 (15.6)

ACE inhibitor 625 (35.4) 615 (34.8) 1240 (35.1)

ARB 1066 (60.3) 1061 (60.1) 2127 (60.2)

Lipid-lowering drug 1418 (80.2) 1416 (80.2) 2834 (80.2)

Diuretic agent 870 (49.2) 910 (51.5) 1780 (50.4)

Insulin 1083 (61.3) 1085 (61.4) 2168 (61.4)

* Plus–minus values are means ±SD. For all characteristics except the urinary albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR), baseline was defined as the eligible assessment associated with the randomization visit if it was performed before or at the date of first dose. If the assessment was missing or performed after the date of first dose, the assessment from the screening visit was used. Percentages may not total 100 because of rounding. ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, and SGLT2 sodium–glucose cotrans- porter 2.

† Race and ethnic group were reported by the participants. “Other” includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and “not reported.”

‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § Smoking was defined as smoking at least one cigarette or the equivalent daily. ¶ For eGFR, the baseline assessment is defined as the mean of the two assessments from the randomization visit and

the screening visit. If only one of the assessments was available, it was used as the baseline assessment. The mean eGFR and the eGFR categories are based on the serum creatinine level and the Chronic Kidney Disease Epidemiology Collaboration 2009 equation.

‖ The urinary albumin-to-creatinine ratio was calculated with albumin measured in milligrams and creatinine measured in grams.

** Albuminuria categories are based on the urinary albumin-to-creatinine ratio, and the baseline assessment is defined as the mean of the two assessments from the randomization visit. If only one of the assessments was available, it was used as the baseline assessment. Normoalbuminuria is defined by a urinary albumin-to-creatinine ratio of less than 30, microalbuminuria by a ratio of at least 30 and less than 300, and macroalbuminuria by a ratio of 300 or greater.

Table 1. (Continued.)

n engl j med 391;2 nejm.org July 11, 2024114

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

6 12 18 24 42 48

Months since Randomization

A First Major Kidney Disease Event

Hazard ratio, 0.76 (95% CI, 0.66–0.88) P=0.0003

Placebo Semaglutide

1766 1767

1736 1738

1682 1693

1605 1640

1516 1572

1408 1489

30 25

5 10 15

0 0 6 12 18 24 42 4830 36

1048 1131

660 742

354 392

Pe rc

en ta

ge o

f P ar

tic ip

an ts

100

0 0

Pe rc

en ta

ge o

f P ar

tic ip

an ts

100

0 0

Pe rc

en ta

ge o

f P ar

tic ip

an ts

100

0 0

No. at Risk

Pe rc

en ta

ge o

f P ar

tic ip

an ts

100

0 0 6 12 18 24 42 48

Months since Randomization

B First Kidney-Specific Component Event

Hazard ratio, 0.79 (95% CI, 0.66–0.94)

Difference in annual slope, 1.16 ml/min/1.73 m2/yr (95% CI, 0.86–1.47)

P<0.001

Placebo Semaglutide

1766 1767

1736 1738

1682 1693

1605 1640

1516 1572

1408 1489

0 0 6 12 18 24 42 4830 36

1048 1131

660 742

354 392

No. at Risk

6 12 18 24 42 48

Months since Randomization

C Death from Cardiovascular Causes

Hazard ratio, 0.71 (95% CI, 0.56–0.89)

1766 1767

1737 1739

1697 1703

1641 1665

1601 1627

1544 1583

0 0 6 12 18 24 42 4830 36

1185 1234

772 838

437 460

e G

FR (m

l/ m

in /1

.7 3

m 2 )

0 0 12 52 104 208

Weeks since Randomization

D Total eGFR Slope

Placebo Semaglutide

1766 1766

1663 1665

1490 1521

1609 1606

1573 1590

1441 1468

1284 1345

876 952

156

609 651

199 218

No. at Risk

6 12 18 24 42 48

Months since Randomization

E First Major Cardiovascular Event

Hazard ratio, 0.82 (95% CI, 0.68–0.98) P=0.029

1766 1767

1721 1725

1663 1672

1583 1622

1535 1575

1478 1515

0 0 6 12 18 24 42 4830 36

1133 1176

731 793

418 430

Pe rc

en ta

ge o

f P ar

tic ip

an ts

100

0 0 6 12 18 24 42 48

Months since Randomization

F Death from Any Cause

Hazard ratio, 0.80 (95% CI, 0.67–0.95) P=0.01

Placebo Semaglutide

1766 1767

1737 1739

1697 1703

1641 1665

1601 1627

1544 1583

0 0 6 12 18 24 42 4830 36

The post With the attached powerpoint as the example, use the information from the attached journal and journal club and create a separate powerpoint that addresse first appeared on Nurse Essays Online.

Related posts:

Related Posts

GET HELP WITH YOUR HOMEWORK PAPERS @ 25% OFF